Numerous systems and techniques have been developed to improve the efficacy and convenience of invasive and non-invasive drug delivery systems. Techniques for delivering drugs include oral administration, direct injection into body tissues, intravenous administration, and transdermal and iontophoretic delivery through the skin. Each type of drug delivery system has its own advantages and disadvantages when compared to the various other delivery systems, and efficacy of the system typically depends on the type of drug and its amenability to the particular delivery technique.
In many cases, drugs such as pharmaceuticals may be administered orally, and the pharmaceutical is designed to be released for absorption by the highly permeable lining of the gastrontestinal system. While advantages of oral ingestion include ease of administration, disadvantages include poor bio-availability due to high “first pass” liver metabolism, the potential for liver toxicity, and the likelihood of drug breakdown and degradation due to digestive processes prior to absorption in the blood stream. Precise control of the release of orally administered drugs is also an issue. Direct injection, using either a hypodermic needle or an injection gun, while allowing for accurate dosing, is not ideal for continuous and convenient drug administration over an extended time period, and may cause recurring pain, trauma and risk of infection to a patient. Commonly used intravenous drug delivery techniques solve the problems of continuous drug administration, but may disadvantageously restrict the patient's mobility. Conventional transdermal systems typically allow for unrestricted patient mobility, but suffer in terms of the types of drugs that can readily diffuse across the relatively impermeable barrier layers of the skin. The stratum corneum layer, in particular, provides the bulk of the resistance to drug permeability. Thus, for drugs in which it is acceptable to administer low dosages over prolonged periods of time, transdermal delivery may prove useful. For the vast majority of drugs, however, this method is not satisfactory due to the low rate at which the drug is absorbed.
In an effort to improve the convenience of drug delivery, provide accurate dosing, and improve drug efficacy, various attempts have been made to improve invasive and non-invasive drug delivery systems. One class of techniques for overcoming the resistive barriers imposed by intact skin is assisted diffusion of a drug through the skin by “electrotransport” processes. Using the principles of electrotransport, a direct electrical current or an electrical potential gradient is used to actively transport the drug transcutaneously into the body.
One method of using electrotransport processes for transdermal drug delivery is known as “iontophoresis.” In iontophoresis, the permeation rate (or “flux”) of a charged drug compound through the skin surface is controlled by the application of an electrical potential directly across the skin's surface to facilitate the diffusion of a drug across the stratum corneum and into the dermal layers. The efficacy of this process thus depends upon ionizable pharmaceuticals or other drugs (e.g., salts of a pharmaceutical or other drug which, when dissolved, form charged ions).
A second type of iontophoretic electrotransport process called “iontophoretic electroosmosis,” involving the transdermal flux of a liquid solvent containing an uncharged drug or pharmaceutical agent, has been recognized as a means for delivery of an uncharged drug or agent into the body. Electroosmosis, in which the solvent convectively moves through a “charged pore” in response to the preferential passage of counter ions, can be induced by the presence of an electric field imposed across the skin by the active electrode of an iontophoretic device.
A third type of electrotransport is known as “electroporation.” Electroporation can be used for drug or other agent transport by altering lipid bilayer permeability through the formation of transiently existing pores in the skin membranes.
At any given time during electrically assisted drug delivery, more than one of these electrotransport processes may be occurring simultaneously to some extent. The composition of the stratum corneum, however, is such that its inherent resistance to the flow of electrons is relatively high in comparison to other underlying body tissue (e.g., the further layers of the epidermis and the blood vessels therein). Thus, for certain types of drugs (e.g., some drugs which must remain electrically neutral to retain activity), and especially in the case of large molecule drugs, conventional electrotransport processes through the skin may not result in effective drug delivery. For example, the relatively large size of many protein and peptide molecules make electrotransport exceedingly difficult. Although an increased level of current may assist the protein and peptide molecules across the stratum corneum, such transport may occur at the expense of damaging the molecules (through electric degradation) and/or burning or irritating the skin.
Iontophoresis is typically carried out by establishing an electrical potential using a direct current (DC) between first electrode 18 and second electrode 20. When a voltage is applied from electrodes 18, 20 across the skin tissue surface 30, the current flows from first electrode 18 through the ionized drug solution in reservoir 22, into the skin tissue surface 30, and then back to the second electrode 20, thus creating an electrical circuit by way of body tissues. More specifically, upon activation of iontophoretic system 16, the charged drug is repelled by first electrode 18 through the skin tissue surface 30 (as indicated by the arrows), thereby initiating drug transport by electrostatic repulsion, ionic conduction, and other cooperating electrotransport processes. Thus, positively charged electrodes (anodes) can be used to drive negatively charged drugs, and negatively charged electrodes (cathodes) can be used to drive positively charged drugs.
A typical electrotransport system 16 for the iontophoretic delivery of a drug is shown in FIG. 1. In conventional iontophoresis, a reservoir 22 is provided on a skin tissue surface 30 to serve as a container for a solution of an ionized drug to be electrically transported. A first electrode 18 of a first polarity (e.g., an anode) is placed adjacent the reservoir 22, while a second electrode 20 of a second polarity (e.g., a cathode) is placed in contact with an area of the skin tissue surface 30 which is spaced apart from reservoir 22. A connecting wire 24, and an external power supply (battery) 26 extend between electrodes 18, 20. An ion-conducting adhesive 28 is situated under each electrode 18, 20 for stabilization of the electrodes. Electrolytes are typically added to the solution containing the ionized drug so that current can be easily conducted. A selectively permeable membrane (not shown) may further be placed under electrode 18 to allow for selective flow of particular types of charged and uncharged species into tissue surface 30. A voltage source 24, typically a battery, supplies direct electric current by conductive wires 26 extending to the electrodes.
Iontophoresis is typically carried out by establishing an electrical potential using a direct current (DC) between first electrode 18 and second electrode 20. When a voltage is applied from electrodes 18, 20 across the skin tissue surface 30, the current flows from a first electrode 18 through the ionized drug solution in reservoir 22, into the skin surface 30, and then back to the second electrode 20, thus creating an electrical current by way of body tissues. More specifically, upon activation of iontophoretic system 16, the charged drug is repelled by first electrode 18 through the skin tissue surface 30 (as indicated by the arrows), thereby initiating drug transport by electrostatic repulsion, ionic conduction, and other cooperating electrotransport processes. Thus, positively charged electrodes (anodes) can be used to drive negatively charged drugs, and negatively charged electrodes (cathodes) can be used to drive positively charged drugs.
The electrode driving the ionized drug is commonly called the “donor,” or “active,” electrode, while the electrode closing the circuit is commonly called the “counter,” or “return,” electrode. Under alternative configurations, both the anode and the cathode can be used to deliver drugs of the opposite charge. In such a case, both electrodes are considered active or donor electrodes.
Dependent upon molecule size and other factors, neutral drug molecules can also be moved by the application of electrical current, although to a lesser extent than ionized drug molecules, by the forces of electroosmosis and electroporation. During the application of the voltage from electrodes 18, 20, the electrotransport process will steadily continue, with transport abruptly decreasing when the driving force of electrical potential is discontinued.
Exemplary iontophoretic systems are disclosed in U.S. Pat. No. 5,618,265 to Myers et al. and U.S. Pat. Nos. 5,647,844 and 4,927,408 to Haak et al. Other patents discussing a variety of iontophoresis systems, iontophoresis electrodes, and/or methods of iontophoretically administering medicament ions include U.S. Pat. No. 4,250,878 to Jacobsen et al., U.S. Pat. No. 4,474,570 to Ariura et al., U.S. Pat. No. 4,557,723 to Sibalis, U.S. Pat. No. 4,744,787 to Phipps et al., U.S. Pat. No. 4,752,285 to Petelenz et al., U.S. Pat. No. 4,820,263 to Spevak et al., U.S. Pat. No. 4,886,489 to Jacobsen et al., U.S. Pat. No. 4,973,303 to Johnson et al., and U.S. Pat. No. 5,125,894 to Phipps et al., all of which are incorporated herein by this reference.
A continuing need exists to develop drug delivery devices with improved characteristics. Prior art electrotransport transdermal drug delivery devices, while offering convenience in the form of continuous drug dosage and increased mobility for a subject, are still somewhat limited in terms of the efficient delivery of many drugs through the resistive barrier of the stratum corneum. Therefore, a need exists in the art for improved drug delivery systems which are efficacious and site-directed.